晚期大肠癌的个体化治疗ppt课件

1、0Individualized Treatments for Advanced Colorectal Cancer:The KRAS StoryDavid Z. Chang, MD, PhDUT MD Anderson Cancer Center张张 宗宗 圣圣CSCO Annual Meeting 20211Targeted therapies have improved clinical outcome of mCRCNeed judicious use of these agents: when, howMany questions remainingHow to overcome th

2、e high cost Treatments need to be individualized: biomarkers and genetic signatures21st biomarker for individualized therapy for colorectal cancer: KRAS status predicts responsiveness (or lack of responsiveness) to EGFR targeted therapies3198019851990199520002005CapecitabineOxaliplatinCetuximabBevac

3、izumabIrinotecan5-FUPanitumumabMedian SurvivalBSC: 4-6 months5FU: 10-14 months5FU/OX/Iri: 20 months+ targeted therapy: 30 months?45RANDOMIZECetuximab + irinotecanCetuximab (initial dose, 400 mg/m2 then weekly infusion 250 mg/m2) + irinotecan (same as prestudy therapy)(n=218)N=329Patients with mCRC w

4、ho progressed during or within 3 mo after irinotecanEGFR+ CRC Histamine receptor antagonist premedication given before at least the first cetuximab infusion.Cetuximab (initial dose, 400 mg/m2 then weekly infusion 250 mg/m2)(n=111)Cunningham D, et al. N Engl J Med. 2004;351:337-345.605101520250123456

5、22.9%5.7 mo4.2 mo10.8%Objective Response RateMedian Duration of Response Cetuximab with irinotecan (n=218)Cetuximab as a single agent (n=111)P=0.007Cunningham D, et al. N Engl J Med. 2004;351:337-345.7RANDOMIZEN=1298Patients with CRC who progressed on 5FU, Oxaliplatin, GFR + IrinotecanCetuximab + Ir

6、inotecanJonker et al. AACR 2007. Abstract 3556.8PROPORTION PROGRESSION FREE0.00.20.40.60.81.003691215184.0 mo4.0 mo2.6 mo2.6 moMONTHSMONTHSHR = 0.692 HR = 0.692 95% CI = 0.617 95% CI = 0.617 0.7760.776CETUXIMAB + IRINOTECAN; N = 648CETUXIMAB + IRINOTECAN; N = 648IRINOTECAN ALONE; N = 650IRINOTECAN A

7、LONE; N = 650STRATIFIED LOGRANK PSTRATIFIED LOGRANK P- -VALUE = 0.0001VALUE = 0.0001Progression Free SurvivalProgression Free SurvivalPROPORTION ALIVEPROPORTION ALIVE0.00.00.10.10.20.20.30.30.40.40.50.50.60.60.70.70.80.80.90.91.01.0MONTHSMONTHS0 03 36 69 91212151518182121242427273030333336363939HR =

8、 0.975 HR = 0.975 (95.03% CI = 0.854 (95.03% CI = 0.854 1.114)1.114)CETUXIMAB + IRINOTECAN; N = 648CETUXIMAB + IRINOTECAN; N = 648Median OS = 10.71 moMedian OS = 10.71 moCETUXIMAB + IRINOTECAN; N = 648CETUXIMAB + IRINOTECAN; N = 648Median OS = 10.71 moMedian OS = 10.71 moIRINOTECAN; N = 650IRINOTECA

9、N; N = 650Median OS = 9.99 moMedian OS = 9.99 moIRINOTECAN; N = 650IRINOTECAN; N = 650Median OS = 9.99 moMedian OS = 9.99 moSTRATIFIED LOGRANK PSTRATIFIED LOGRANK P- -VALUE = 0.7115VALUE = 0.7115Overall SurvivalOverall Survival9RANDOMIZEFOLFIRI + cetuximab(608) First-line mCRCFOLFIRI(609)Cutsem et a

10、I, et al. ASCO 2007. 4000.10Cetuximab+FOLFIRI(N=608)Irinotecan(N=609)P ValuePFS8.98 0.036Response Rate (%) 46.9%38.7% 0.00511Peeters M, et al. AACR 2006. Abstract CP-1.RANDOMIZEPanitumumab (6 mg/kg q2 wk) + BSC (n=231) N=463 Patients third-line mCRC EGFR expression requiredOptional panitumumab cross

11、over study(n=174)Best supportive care(n=232)PDPDStratification based on ECOG score, geographic region12PFS longer with panitumumab vs BSCHR, 0.54 (95% CI, 0.44-0.66; P0.000000001)*P0.0001.Peeters M, et al. AACR 2006. Abstract CP-1.Panitumumab (n=231)BSC (n=232)PR, n (%)19 (8)*0 (0)SD, n (%)64 (28)24

12、 (10)Median duration response, wk (range)17 (4+-40+)n/a1314EGF/EGFR PathwayProliferationApoptosis ResistanceTranscriptionShcPI3KRafMEKK-1MEKMKK-7JNKERKRasmTORGrb2AKTSos-1EGFR15161718RANDOMIZEFOLFIRI + cetuximab(608) First-line mCRCFOLFIRI(609)Cutsem et aI, et al. ASCO 2007. 4000.1900.20.40.60.81.004

13、812MosPFS Estimate16Cetuximab + FOLFIRIFOLFIRIKRAS mutation (n = 192) HR: 1.07; P = .47261014Median PFS cetuximab + FOLIFIRI: 7.6 mosMedian PFS FOLIFIRI: 8.1 mos0.10.30.50.70.9Van Cutsem E, et al. ASCO 2021. Abstract 2. Reproduced with permission.2000.20.40.60.81.004812Mos18Cetuximab + FOLFIRIFOLFIR

14、IWT KRAS (n = 348): HR: 0.68; P = .017261014Median PFS cetuximab + FOLIFIRI: 9.9 mosMedian PFS FOLIFIRI: 8.7 mos0.10.30.50.70.9161-yr PFS rate: 43%Van Cutsem E, et al. ASCO 2021. Abstract 2. Reproduced with permission.1-yr PFS rate: 25%PFS Estimate21ITT PopulationK-ras Wild TypeK-ras MutationFOLFIRI

15、FOLFIRIFOLFIRIWith ERBITUX No ERBITUXWith ERBITUX No ERBITUXWith ERBITUX No ERBITUX# of Patients 599 599 172 176 105 87Overall Response Rate 47% 39% p=0.004 59% 43% p=0.003 36% 40% p=0.46Median PFS 8.9 mos 8.0 mos Hazard Ratio: 0.85 p=0.05 9.9 mos 8.7 mos Hazard Ratio: 0.68 p=0.02 7.6 mos 8.1 mos Ha

16、zard Ratio: 1.07 p=0.75222324Genomic DNA was isolated from archived tumor materialKRAS mutation status of codons 12/13 was determined using a sensitive, quantitative PCR-based assay Population with tissue available for KRAS analysis (n = 233) was representative of overall ITT population (n = 337) in

17、 terms of demographics and efficacy parametersKRAS mutations detected in 42% (99/233) of evaluable samplesBokemeyer C, et al. ASCO 2021. Abstract 4000.2526ITT PopulationK-ras Wild TypeK-ras MutationFOLFOXFOLFOXFOLFOXWith ERBITUX No ERBITUXWith ERBITUX No ERBITUXWith ERBITUX No ERBITUX# of Patients 1

18、69 168 61 73 52 47Overall Response Rate 46% 36% p=0.006 61% 37% p=0.01 33% 49% p=0.11Median PFS 7.2 mos 7.2 mos Hazard Ratio: 0.93 p=NSS 7.7 mos 7.2 mos Hazard Ratio: 0.57 p=0.02 5.5 mos 8.6 mos Hazard Ratio: 1.83 p=0.02272829303132Cetuximab + bevacizumab/capecitabine/oxaliplatin decreased PFS witho

19、ut affecting OSAlthough manageable, cetuximab + bevacizumab/ chemotherapy increases skin toxicity and diarrhea adverse eventsTreatment discontinuation due to toxicity did not differ between armsNegative interaction between anti-VEGF and anti-EGFR cannot be discountedPunt CJ, et al. J Clin Oncol. 202

20、1;26(May 20 suppl):abstr LBA4011.3334Patients with irinotecan-refractory metastatic cancerCetuximab 400 mg/m2 initial dose then 250 mg/m2/wk + Irinotecan 180 mg/m2 Q2WControl Standard Cetuximab regimen (250 mg/m2/wk)(n = 23)Dose Escalation Cetuximab dose increasesof 50 mg/m2 Q2W up to maximum 500 mg

21、/m2/wk(n = 31)Nonrandomized Standard Cetuximab regimen (250 mg/m2/wk)SCREENINGDay 22Randomized:skin toxicity grade 0/1Not eligible for randomization:skin toxicity grade 2/3All patients continued to receive irinotecan Treatment until progression, unacceptable toxicity or withdrawal of consentSkin and

22、 tumor biopsy at baseline, Week 3, and at maximum cetuximab dose in dose-escalation armTejpar S, et al. ASCO 2021. Abstract 4001.3500.20.40.60.81.00200400600DaysPFS Estimate800P .0001KRAS mutantWT KRASKRAS mutation present83 days (95% CI: 75.9-90.2)173 days (95% CI: 141.3-204.7)Tejpar S, et al. ASCO

23、 2021. Abstract 4001. Reproduced with permission.360.00.20.40.60.81.002004006008000.00.20.40.60.81.002004006008000.00.20.40.60.81.00200400600800DaysDaysDaysKRAS mutantWT KRASControlKRAS mutation presentP = .014KRAS mutantWT KRASDose EscalationKRAS mutation presentKRAS mutantWT KRASNonrandomizedKRAS

24、mutation presentP .001P = .020Tejpar S, et al. ASCO 2021. Abstract 4001. Reproduced with permission.PFS EstimatePFS EstimatePFS Estimate37Dose escalation of cetuximab did increase response rateAmong patients without rash receiving, KRAS status still predicted response to cetuximabAmong patients rece

25、iving escalated dose of cetuximab (to rash), KRAS MT still did not respond Higher dose did not overcome KRAS statusSkin rash and KRAS are independent predictors38Kras status is a predictive marker for EGFR targeted therapyPatients with wild-type Kras may benefit from EGFR targeted therapyPatients with mutant Kras may NOT benefit from EGFR targeted therapyCetuximab may have detrimental effects in patients with mutant KrasWhenever considering to use EGFR targeted therapy, Kras status should be tested.39What to do with current trials invol